C-type lectin-like-1 (CLL-1, also known as CLEC-1, CLEC12A, MICL, Dendritic Cell-Associated Lectin-1 (DCAL-1), and DCAL-2) is a glycoprotein receptor and member of a family of C-type lectin-like receptors involved in the regulation of cell proliferation and immune regulation. CLL-1 is expressed in hematopoietic cells, primarily on innate immune cells including monocytes, granulocytes, dendritic cells, as well as myeloid progenitor cells. Van Rhenen et al., Blood 2007:110(7). CLL-1 has been implicated in the regulation of myeloid cell proliferation and differentiation (Bakker et al., Cancer Res. 64:8443-8450 (2004); Marshall et al., J. Biol. Chem. 279:14792-14802 (2004)), and is present on acute myeloid (myelogenous) leukemia (AML) cells as well as on leukemic stem cells (Zhao et al., Haematologica 2010, 95(1):71-78).
Accordingly, CLL-1 has been implicated in multiple diseases, including but not limited to, acute myeloid (myelogenous) leukemia (AML), chronic myeloid (myelogenous) leukemia (CML), chronic myelomonocytic leukemia (CMML), juvenile myelomonocytic leukemia, atypical chronic myeloid leukemia, acute promyelocytic leukemia (APL), acute monocytic leukemia, acute monoblastic leukemia, acute erythroid leukemia, acute megakaryoblastic leukemia, myelodysplastic syndrome (MDS), myeloproliferative disorder, myeloid neoplasm, myeloid sarcoma), Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN), or combinations thereof.
CLL-1 may additionally play a role in inflammatory or autoimmune diseases such as rheumatoid arthritis, psoriasis, allergies, asthma, Crohn's disease, IBD, IBS, fibromyalga, mastocytosis, and Celiac disease.
Human CLL-1 protein comprises a polypeptide of the following amino acid sequence:
(SEQ ID NO. 140)MSEEVTYADLQFQNSSEMEKIPEIGKFGEKAPPAPSHVWRPAALFLTLLC LLLLIGLGVLASMFHVTLKIEMKKMNKLQNISEELQRNISLQLMSNMNIS NKIRNLSTTLQTIATKLCRELYSKEQEHKCKPCPRRWIWHKDSCYFLSDD VQTWQESKMACAAQNASLLKINNKNALEFIKSQSRSYDYWLGLSPEEDST RGMRVDNIINSSAWVIRNAPDLNNMYCGYINRLYVQYYHCTYKKRMICEK MANPVQLGSTYFREA.
Additional sequence information is contained in the CLL-1 Uniprot listing at: www.uniprot.orq/uniprot/Q5QGZ9, as well as NCBI Reference Sequence NP_612210.4 (www.ncbi.nlm.nih.gov/protein/NP_612210.4).
When referring to CLL-1, it will be appreciated that reference thereto encompasses fragments thereof, as well as related polypeptides, which include, but are not limited to, allelic variants, splice variants, derivative variants, substitution variants, deletion variants, and/or insertion variants including the addition of an N-terminal methionine, fusion polypeptides, and interspecies homologs. In certain embodiments, a CLL-1 polypeptide includes terminal residues, such as, but not limited to, leader sequence residues, targeting residues, amino terminal methionine residues, lysine residues, tag residues and/or fusion protein residues.
Certain antibodies to CLL-1 are described in U.S. Pat. No. 8,536,310 and in U.S. Pat. No. 9,163,090.
Engineered immune cells have been shown to possess desired qualities in therapeutic treatments, particularly in oncology. Two main types of engineered immune cells are those that contain chimeric antigen receptors (termed “CARs” or “CAR-Ts”) and T-cell receptors (“TCRs”). These engineered cells are engineered to endow them with antigen specificity while retaining or enhancing their ability to recognize and kill a target cell. Chimeric antigen receptors may comprise, for example, (i) an antigen-specific component (“antigen binding molecule”), (ii) an extracellular domain, (iii) one or more costimulatory domains, and (iv) one or more activating domains. Each domain may be heterogeneous, that is, comprised of sequences derived from (or corresponding to) different protein chains. Chimeric antigen receptor-expressing immune cells (such as T cells) may be used in various therapies, including cancer therapies. It will be appreciated that costimulating domains may be used to enhance the activation of CAR-expressing cells against target antigens, and therefore increase the potency of adoptive immunotherapy.
Certain CARs to CLL-1 have been described in, e.g., U.S. Patent Application 20160051651 (PCT US2015/041337).
T cells can be engineered to possess specificity to one or more desired targets. For example, T cells can be transduced with DNA or other genetic material encoding an antigen binding molecule, such as one or more single chain variable fragment (“scFv”) of an antibody, in conjunction with one or more signaling molecules, and/or one or more activating domains, such as CD3 zeta.
In addition to the CAR-T cells' ability to recognize and destroy the targeted cells, successful T cell therapy benefits from the CAR-T cells' ability to persist and maintain the ability to proliferate in response to antigen.
T cell receptors (TCRs) are molecules found on the surface of T cells that are responsible for recognizing antigen fragments as peptides bound to major histocompatibility complex (MHC) molecules. The TCR is comprised of two different protein chains—in approximately 95% of human TCRs, the TCR consists of an alpha (α) and beta (β) chain. In approximately 5% of human T cells the TCR consists of gamma and delta (γ/δ) chains. Each chain is composed of two extracellular domains: a variable (V) region and a constant (C) region, both of the immunoglobulin superfamily. As in other immunoglobulins, the variable domains of the TCR α-chain and β-chain (or gamma and delta (γ/δ) chains) each have three hypervariable or complementarity determining regions (CDRs). When the TCR engages with antigenic peptide and MHC (peptide/MHC), the T cell becomes activated, enabling it to attack and destroy the target cell.
However, current therapies have shown varying levels of effectiveness with undesired side effects. Therefore, a need exists to identify novel and improved therapies for treating CLL-1 related diseases and disorders.